The proliferation, differentiation and destruction of cells and tissues for maintaining body homeostasis is controlled by a balance of the interactions between various cell-stimulating factors and the cells in the extracellular matrix. When an imbalance occurs in this regulation, various diseases comprising an apoptosis or non-activation to stop signal of proliferation, a nutrition supply by continuous angiogenesis, a malignant tumor expressed by permeation to surrounding tissues and a metastasis occurs.
Angiogenesis comprises all of a degradation of cell basement membrane, a cell movement, an invasion to extra-cell matrix, a cell proliferation, and a synthesis of endothelial cavity of capillary. For inhibition of these, there are a direct method to targeting vascular endothelial cells and an indirect method to targeting cancer cells or surrounding cells which make angiogenesis factors. Studies which aim to develop an anti-body protein to inhibit angiogenesis factor activity or a low molecular material to block the receptor has been largely carried out.
Angiogenesis occurs through a series of steps including a movement and a division of endothelial cells to make blood walls. About 15 kinds of proteins to activate growth and movement endothelial cells are known and they regulate angiogenesis. Therefore, angiogenesis can be inhibited by an inhibitor for inhibiting activation proteins such as angiogenin, epithelial growth factor, estrogen, fibroblast growth factor, interleukin 8, prostaglandin E1 and E2, tumor necrosis factor, or G-CSF (granulocyte colony-stimulating factor).
Heat shock proteins (HSPs) are molecular chaperones which play critical roles in maintaining homeostasis. They are critical for cell survival especially under stresses such as hypoxia. HSPs, especially HSP90 and HSP 70, are highly expressed in a wide range of tumors [Morano K A, Annals of the New York Academy of Sciences, 1113:1-14, 2007; Calderwood S K et al, Trends in biochemical sciences, 31:164-72, 2006]. The expression of several HSPs has been shown to be correlated with tumor cell proliferation, differentiation and apoptosis in several cancers, indicating that HSPs play crucial roles of cancer cell survival due to their cytoprotective role Overexpression of HSP70 induces tumorigenicity to mouse fibrosarcoma cells and overexpression of HSP70 in T-cells of transgenic mice resulted in an increase of T-cell lymphoma in these mice [Jaattela M, International journal of cancer Journal international du cancer, 60:689-93, 1995; Seo J S et al, Biochemical and biophysical research communications, 218:582-7, 1996; Volloch V Z et al, Oncogene, 18:3648-51, 1999; Murphy M E, Carcinogenesis, 34:1181-8, 2013]. Especially, HSP70 has been known to play a crucial role in protecting cells from apoptosis. Besides, overexpression of HSP expression seems to be involved in angiogenesis, invasion, and metastasis [Calderwood S K et al, Trends in biochemical sciences, 31:164-72. 2006; Zhou J et al, The Journal of biological chemistry, 279: 13506-13, 2004; Bruns A F et al, PloS one, 7:e48539, 2012; Sun J et al, Arteriosclerosis, thrombosis and vascular biology. 24:2238-44, 2004; Gong W, et al, Oncology reports, 2013; Eustace B K et al, Cell cycle, 3:1098-100, 2004; Eustace B K et al, Nature cell biology, 6:507-14, 2004].
Based on a theory that cancer can be cured by inhibition of cancer growth and metastasis through blockage of vascularization for supplying oxygen and nutrition to cells, drugs for anti-angiogenesis have been developed for treating not only anti-cancer, but also arthritis, diabetic retinopathy, chronic inflammation, and ischemic heart disease. The treatment of anti-angiogenesis directly inhibits tumor growth and metastasis and indirectly normalize the tumor vascular circumstances to improve effect of treatment which delivers the biological and chemical drugs effectively and refine hypoxia circumstance.
Therefore, there is a need for the development of anti-angiogenesis drugs to treat or prevent malignant tumors, various diseases (arthritis, diabetic retinopathy, chronic inflammation, ischemic heart diseases etc.), excessive angiogenesis related tumor (cancer), heart vascular diseases (for example, atherosclerosis), chronic inflammation (for example, rheumatic arthritis or Crone's disease), diabetics (for example, diabetic retinopathy), psoriasis, and endometriosis.